Scientists have ethical and regulatory commitments to minimize pain and distress during their use of sentient laboratory animals. Here I discuss pain as a special form of distress and the long history of ethical and regulatory standards calling on scientists to prevent, minimize, treat or terminate animal pain. Scientists, veterinarians, and IACUC face 2 challenges: knowledge of effective analgesic doses and regimens for all sexes, ages and genotypes of rodent is incomplete, and concerns regarding the effects of analgesic drugs on research outcomes push scientists to request approval to withhold analgesics and leave animal pain unalleviated. IACUC thus conduct what I call an 'ethics of uncertainty,' in which they factor in the limits of available ethically relevant information on the amount of expected animal suffering, the usefulness of analgesics to mitigate this suffering, and the eventual benefits that come from the research. IACUC must factor in current limitations in severity assessments of various experimental manipulations in various strains, inaccurate pain diagnosis, in known effective analgesic and other refinements, and on effects of pain medications and untreated pain on data outcomes, when deciding to allow potentially painful experiments and animal care practices. This article focuses on 3 areas of concern: the limits of veterinary "professional judgment" when the animal model's degree of pain and the efficacy of pain medications are not yet known; the review of proposals with known, unalleviated significant pain and distress (that is, Category E experiments); and the attempt to review the balance between animal welfare harms and scientific objectives. I propose no new regulations, standards, or ethical norms herein but rather explore some of the implications when existing ethical principles are applied to evolving scientific knowledge (and vice versa). I conclude that applying current animal pain management knowledge to prevailing ethical principles will shift IACUC toward greater caution in allowing potentially painful animal experiments, with heightened caution regarding the ability of analgesics to mitigate the animals' pain.